A pharmacologically quantified and reproducible animal model of barbiturate dependency, that was developed in this laboratory, will be used for a continued study of barbiturate dependency and withdrawal. Our initial aim is to apply this method in determining pharmacologic factors which contribute to the development of tolerance, alterations in pharmacokinetics and the production of dependency by (a) altering levels of chronic pentobarbital dosing (b) varying frequencies of administration and (c) changing durations of dosing. These same experimental variables will be considered in determining the tolerance, pharmacokinetic and withdrawal characteristics of other barbiturates and other CNS depressants, including ethanol and benzodiazepines. Using this dependency model, several possible drug therapies for withdrawal will be evaluated in whole animal and in an in vivo neuronal system. The effectiveness of benzodiazepines, a GABA modulator and steroid anesthetics will be explored. Neurophysiologic alterations during withdrawal will be examined in segmental reflex pathways. Our studies have uncovered certain synaptic vulnerabilities during barbiturate withdrawal. The neuronal loci and mechanisms of these will be investigated. Further, the neurophysiologic effects of ethanol and barbiturate withdrawals will be compared with respect to the neuronal loci involved and particular differences will be explored. Selective correction of neuronal disorders by potentially useful therapies will be tested. Studies of chronic barbiturate and ethanol effects and withdrawal on the normal sleep cycle will be continued. This offers a new dimension for studies of dependency-withdrawal effects on sleep, because, in this model, the dependency withdrawal states have been quantitatively defined. Recently, we have found that chronically denervated spinal segmental reflex arcs of rats can be made physically dependent to ethanol and barbiturates. Characteristics and quantifiable hind limb movements were produced after abrupt termination of either barbiturate or ethanol. This system will be quantitatively defined in order to serve as one of the new model systems for the study of CNS depressant drug dependency.